Adds to evidence against aggressive treatment

Action Points

Note that this meta-analysis of studies examining dose-escalation of radiation therapy for prostate cancer found that the modality does reduce the risk of biochemical failure, but has no effect on overall mortality.

Be aware that the study involved only men with localized prostate cancer.

A review of 12 randomized controlled trials from 1990 or later of escalating external-beam radiation therapy (EBRT) in 6,884 men with localized prostate cancer found improvement in freedom from biochemical failure (FFBF) but not in overall survival, cancer metastasis, or cancer-specific death at 5 and 10 years.

These results add to the evidence questioning aggressive local treatment strategies in men with low-risk disease.

Published in the American Journal of Clinical Oncology, the meta-analysis found that increasing the biologically equivalent dose (BED) of radiation was associated with an almost 10% increased FFBF – since the 1990s, the primary outcome measure in most EBRT trials for prostate cancer, with failure usually defined as a rise in prostate-specific antigen (PSA) of 2 ng/mL above the nadir achieved after radiation.

The 10-year absolute improvement was 9.6% for low-risk patients and 7.2% for intermediate-risk patients (P<0.05). Dose escalation did not, however, correlate with improvement in overall survival, distant metastases, or cancer-specific mortality at either time point.

"PSA may be a poor surrogate for patient outcome in the contemporary era," wrote radiation oncologist Robert B. Den, MD, of Thomas Jefferson University, Philadelphia, and his co-authors.

And while BED escalation did not correlate with increased acute toxicities, it was associated with increased late gastrointestinal toxicities in patients treated with 3D conventionally fractionated radiation. For late toxicity, 10-Gy increments of BED3 from 98 to 133 were associated with risk differences of 0.4% (P=0.31) and 1.5% (P<0.01) in genitourinary and gastrointestinal toxicities, respectively.

For intensity-modulated radiation therapy patients, with BED3 between 121 and 134 Gy, 10-Gy increments of BED10 were associated with risk differences of 0.4% (P=0.71) and –0.2% (P=0.60) for late genitourinary and gastrointestinal toxicities, respectively.

These findings contrasted with those of an analysis of National Cancer Database patients that found dose-escalated EBRT associated with improved overall survival at 7 years but may have included men with more advanced disease, Den and associates noted.

"In the field of radiation oncology, we often assume that the highest dose that the body can tolerate will be most effective at killing cancer," said Ben in a Jefferson news release. "Our results argue that this may not be the case, at least not with lower-risk prostate cancer patients."

Den added that while dose escalation reduced PSA levels without greater toxicity, radiation may need to be combined with other therapies to improve survival. Den's Jefferson co-author, Adam Dicker, MD, stressed that relying on the PSA test as an outcome proxy may not be as useful as had been thought and that this "has broad implications for the design of future clinical trials and the interpretation of current and previous studies."

The authors recommended that subsequent trials not be powered solely to detect radiotherapy's impact on FFBF: "Future studies should assess other biomarkers; or, novel imaging techniques ... which may help to differentiate benign tissue from recurrence and locate the source of recurrence," they wrote.

The researchers noted that among the meta-analysis's limitations are the lack of individual patient data, such as comorbidities, cancer characteristics, possible salvage treatments received, and quality of life. Additionally, the review was not able to compare biochemical progression between hypofractionated and conventionally fractionated studies since only five of the 12 studies included had a hypofractionated arm.

Furthermore, longer data at 15 and 20 years are needed, and even with almost 7,000 patients, the study may have been underpowered compared with much larger ones drawing on the National Cancer Database.

Commenting on the study for MedPage Today, Anthony L. Zietman, MD, a radiation oncologist at Massachusetts General Hospital in Boston, said that the meta-analysis confirms what clinicians already know: "Higher radiation doses are more likely to eradicate the cancer but, because most of these men were never destined to die from prostate cancer anyhow, overall survival was not improved," he said. "The bottom line is that when treatment is unnecessary in the first place, better treatment is no less unnecessary."

Zietman said that a large British trial comparing radiation, surgery, and active surveillance for prostate cancer will soon appear in the New England Journal of Medicine. "That will be the prostate cancer news event of 2016."

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